Tripe Palms

Tripe palms (TP), initially described by Clarke in 1977, is a rare paraneoplastic dermatosis with roughly 100 cases described in the literature. Clinically, patients present with hyperkeratosis and accentuation of skin ridges on the palms and, at times, the soles. The skin has a rugose, velvety appearance, said to resemble tripe, a food prepared from bovine foregut ( Fig. 1 A). Changes are exaggerated over pressure points, such as the fingertips and thenar and hypothenar eminences. Diffuse involvement of the palms with either a mosslike or honeycomb pattern has been described. Associated pruritus occurs in 25%. When clubbing of the nails is seen with TP (18% of cases), a pulmonary carcinoma should be suspected as the underlying malignancy.

( A ) TP; ( B ) necrolytic migratory erythema; ( C ) Sweet’s syndrome ( D ) necrobiotic xanthogranuloma.

TP is more common in men than women, and is found almost exclusively in adults. There is no known genetic association or racial predilection. Whether TP is a distinct entity or a manifestation of malignant acanthosis nigricans on the palms is contested; some investigators contend that TP, malignant acanthosis nigricans, and the sign of Leser-Trélat (LT) are not separate entities but rather exist on a spectrum. Most cases of TP are associated with malignancy (94% of cases) and malignant acanthosis nigricans frequently coexists (77% of cases). TP frequently develops before the diagnosis of malignancy, but may occur concurrently or after the diagnosis of cancer. When present alone, TP is most commonly associated with pulmonary carcinoma, followed in incidence by gastric carcinoma. However, when present with acanthosis nigricans, a gastric carcinoma is more common. Tumors of the genitourinary tract, tongue, and breast have also been associated with TP.

Treatment is difficult and is primarily aimed at the underlying tumor. In one-third of cases, TP parallels the course of the associated malignancy. Retinoids, emollients, keratolytics, and topical steroids, although reported, are often of limited benefit.

Acanthosis Nigricans

Although benign acanthosis nigricans (typically familial or associated with obesity or endocrinopathy) is common, malignant acanthosis nigricans (MAN) is rare, with roughly 1000 cases reported in the literature. MAN usually occurs in adults more than 40 years of age. There is no known genetic, racial, or gender predilection.

Clinically, MAN usually presents with a sudden onset of symmetric, hyperpigmented, thickened plaques creating a velvety texture. Plaques may be yellow, gray, or black. MAN most commonly affects the nape and sides of the neck, the axillae, inframammary folds, and inguinal creases. Frequently, acrochordons (skin tags) are seen within the plaques. MAN has been associated with florid cutaneous papillomatosis and often occurs in conjunction with TP and/or the sign of LT.

In contrast with benign acanthosis nigricans, MAN is usually extensive and rapidly progressive. Forty-one percent have associated generalized pruritus. With extensive involvement, lesions may involve the areola and umbilicus. Mucosal involvement occurs in 35% of patients with MAN, and may affect the eyes, oral cavity (including lips, gingival, buccal mucosa and palate), esophagus, larynx, and anal and genital mucosa.

MAN may either precede (18%), accompany (61%), or follow (21%) the onset of the internal cancer. Most cases are associated with adenocarcinoma, especially of the gastrointestinal tract (60% stomach), lung, and breast. Cancers of the gallbladder, pancreas, esophagus, liver, prostate, kidney, colon, rectum, uterus, and ovaries have also been reported, as well as hepatocellular cancer and lymphoma.

MAN tends to parallel the course of the associated malignancy. Skin changes usually regress with suppression or removal of underlying malignancy, and, conversely, worsen following relapse. The overall prognosis for most patients with MAN is poor because the associated tumors are usually aggressive with a high mortality.

The Sign of LT

The sign of LT is a rapid appearance or growth of multiple seborrheic keratoses associated with an underlying malignancy. It is named after the surgeons Leser and Trélat who first independently described the occurrence of skin lesions with an internal malignancy in 1890. However, it is now thought that the lesions they were describing were vascular angiomas, and it was Hollander who first associated seborrheic keratoses with malignancy in 1900. Controversy exists regarding the validity of this sign because both seborrheic keratoses and internal malignancy are common in the elderly population, making it difficult to distinguish coincidence from correlation. In addition, determining whether seborrheic keratoses are eruptive can be difficult, because an exact definition is lacking.

Clinically, LT presents as multiple, eruptive seborrheic keratoses primarily on the trunk and extremities. Individual lesions are clinically and pathologically indistinguishable from the common seborrheic keratosis. Pruritus is found 26% to 51% of the time.

The sign of LT is rare, with roughly 100 cases reported to date. The average age of onset is 60 years, although young patients have been reported. There is no gender or racial predilection. Sixty-five percent of patients with LT have a concurrent paraneoplastic dermatosis, with MAN occurring 29% of the time.

Similar to MAN, the most common type of underlying tumors are adenocarcinomas, especially of the gastrointestinal tract (32%). Unlike MAN, lymphoproliferative disorders are the next most commonly associated malignancy, occurring 21% of the time. Both MAN and LT have been associated with aggressive malignancies. Metastases were found 57% of the time when the sign of LT was present.

Although treatment is directed at the underlying malignancy, in 60% of cases of LT, the cutaneous findings do not parallel the course of the cancer. Local treatment of the seborrheic keratoses, such as shave removal or cryotherapy, can be performed for irritating lesions.

Bazex Syndrome (Acrokeratosis Paraneoplastica)

Acrokeratosis paraneoplastica, or Bazex syndrome, is a paraneoplastic process that was named after Bazex in 1965, who described a patient with scaly erythematous lesions of the extremities who had an underlying squamous cell carcinoma of the piriform fossa. Clinically, the lesions present as symmetric psoriasiform plaques, most commonly on the nose, helices, earlobes, and distal extremities. Nail dystrophy is often present, and, in advanced disease, the skin lesions can spread to involve the elbows, knees, thighs, and arms. Palmar and plantar keratoderma, accentuated in areas of pressure, may also be seen. Bullous, vesicular, and pustular lesions have been reported.

Bazex syndrome almost always occurs in men older than 40 years, and predominantly in white men. HLA typing in several cases has shown HLA-A2 and or B8 to be present. A history of smoking or alcohol use is common. The rash often mimics seborrheic dermatitis, lupus erythematosus, or psoriasis, which may lead to underdiagnosis of this syndrome.

Bazex syndrome is always associated with an underlying malignancy. The cutaneous findings most commonly precede the diagnosis of malignancy (two-thirds of the time); however, the eruption may occur simultaneously or after the malignancy is discovered.

The most common types of malignancies associated with Bazex are squamous cell carcinomas (64% of cases) from the upper aerodigestive tract, most commonly from the oral cavity, larynx, pharynx, lung, and esophagus. Lymph node metastases are present in 50% of cases, with some cases presenting with cervical lymph node metastases of unknown primary (16%). Concurrent acquired ichthyosis (AI) and the sign of LT have been reported.

In more than 90% of cases, the cutaneous findings parallel the course of the cancer. Removal of the tumor usually causes regression, and worsening may herald a recurrence. Treatment with keratolytics, topical steroids, and antibiotics does not show improvement in most cases. There have been some reports of improvement with psoralen and ultraviolet A therapy and oral retinoids, but treating the underlying malignancy is the primary management.

Acquired Ichthyosis

Ichthyosis is derived from the Greek word for fish, ichthys , and describes the resemblance of the skin in this disease to fish scales. Ichthyosis can be genetic or acquired, and the acquired forms are secondary to a variety of different drugs and diseases, including malignancy. In 1943, Ronchese first described a patient with Hodgkin disease who later developed AI. Subsequent case reports have described AI as a paraneoplastic dermatosis.

AI most commonly manifests in adulthood and is otherwise difficult to distinguish from the hereditary forms of ichthyosis. Symmetric scaling is seen, which ranges in severity from minor roughness and dryness to severe desquamation and platelike scaling. The color of the scales varies from white to gray to brown, with a diameter ranging from less than 1 mm to greater than 1 cm. It primarily affects the trunk and limbs, typically being accentuated on the extensor surfaces with relative sparing of the flexures. AI usually affects the lower extremities more significantly than the upper extremities. AI may be more common in men than women. There is no reported genetic or racial predilection.

AI usually presents after the diagnosis of the malignancy, but it may present before. The most common associated malignancy is Hodgkin disease, estimated to occur in 60% to 80% of cases. Other lymphoproliferative malignancies and solid organ tumors have been reported. AI has been seen in conjunction with other paraneoplastic dermatoses such as Bazex syndrome, erythema gyratum repens, and dermatomyositis.

As with the other paraneoplastic dermatoses, management of AI is designed to treat the underlying tumor. The course of the disease usually parallels the underlying malignancy, and most cases of tumor remission result in resolution of the ichthyosis. Topical steroids, keratolytics, and oral retinoids have been tried with variable success.

Erythema Gyratum Repens

Erythema gyratum repens (EGR) is derived from the Greek word gyrate , meaning circle, and the Latin word repens , meaning to creep. The first case was reported in 1952 when Gammel described a “knotty cypress wood grain” pruritic eruption associated with adenocarcinoma of the breast that resolved following tumor removal.

Clinically, the eruption involves concentric erythematous rings that develop trailing scale at their edges and advance at a rapid rate (∼1 cm per day). The classic wood-grain scaling is often associated with pruritus, ichthyosis, and palmoplantar keratoderma. At times, a peripheral eosinophilia is seen. Men are affected twice as commonly as women, with an average age of 63 years at onset. All cases but 1 have been described in white people.

EGR is associated with an internal malignancy more than 80% of the time. EGR usually precedes the diagnosis of malignancy by an average of 9 months. Rarely, the skin eruption follows the diagnosis of malignancy. Approximately 33% of patients have an underlying lung cancer, 8% esophageal cancer, 6% breast cancer, and another 6% with an unknown primary. Other solid organ and lymphoproliferative malignancies have been reported.

Although therapies directed at the skin changes are typically ineffective, EGR characteristically improves with successful treatment of the underlying malignancy. Systemic steroids have shown variable success. EGR may resolve immediately before death, possibly because of generalized antemortem immunosuppression.

Necrolytic Migratory Erythema (Glucagonoma Syndrome)

Necrolytic migratory erythema (NME) is a rare cutaneous dermatitis that is most often seen with glucagonoma syndrome. Glucagonoma syndrome is a paraneoplastic syndrome with a characteristic triad of a pancreatic tumor secreting glucagon, hyperglycemia, and NME. In 1942, Becker and colleagues first described the association of an erosive erythema occurring with a pancreatic neoplasm. In 1966, McGavran and colleagues attributed the syndrome to hyperglucagonemia, and, in 1973, the term NME was coined by Wilkinson to describe the characteristic associated cutaneous eruption. In a review of 21 patients with glucagonoma syndrome, all of the patients had NME at one point in their illness, and 67% had NME as the presenting complaint.

Clinically, patients often present emaciated, with a chronic dermatitis of many years. In many instances, they have been misdiagnosed with eczema, acrodermatitis enteropathica, or seborrheic dermatitis on presentation. The skin eruption is characterized by a pattern of spontaneous remissions and exacerbations without identifiable triggering factors. It can be highly pruritic and painful, and most commonly involves the intertriginous areas, perineum, lower extremities, and buttocks. The lesions often begin as erythematous macules, papules, and patches that evolve into annular or circinate well-demarcated plaques. There can be fragile vesicles and bullae in the central portion of the lesions, which leave extensive painful erosions when damaged. Other mucocutaneous manifestations may include angular stomatitis, cheilosis, painful glossitis, blepharitis, conjunctivitis, perianal and genital lesions, alopecia, and nail dystrophy (see Fig. 1 B).

Associated clinical features of the glucagonoma syndrome include weight loss (71%), normocytic anemia (43%–90%), diarrhea (15%–29%), neurologic and psychiatric symptom and signs (20%), and thromboembolic phenomena (11%–14%). Less than 250 cases of NME have been reported in the literature since 1942. The prevalence is equal in men and women, and most commonly presents in the sixth decade of life.

NME is unique among paraneoplastic syndromes, because it is specific for a particular tumor (glucagonoma) when found in the glucagonoma syndrome. Glucagonoma, an α-cell tumor of the pancreas, is most often identified in the body and tail of the pancreas. At least 50% of tumors are metastatic at the time of diagnosis. The most common site for metastasis is the liver, followed by regional lymph nodes, bone, adrenal gland, kidney, and lung. In a recent series, the 10-year survival rate in 233 patients with glucagonomas was 51.6% in those with metastases and 64.3% in those without metastases.

NME has also been reported in the absence of the pancreatic tumor, which has been termed pseudoglucagonoma syndrome. Pseudoglucagonoma is typically seen in association with intestinal malabsorption disorders, cirrhosis, inflammatory bowel disease, and pancreatitis.

Surgical removal of the tumor is the most effective treatment, which may produce rapid clinical resolution of the rash. Supplementation with zinc, amino acids, and essential fatty acids, and long-acting somatostatin analogues such as octreotide, may also be beneficial.

Dermatomyositis

Dermatomyositis (DM) is an idiopathic inflammatory myopathy often causing patients to present with characteristic cutaneous findings and proximal muscle weakness. The association of dermatomyositis with malignancy was first reported by Stertz in 1916, who described a patient with proximal muscle weakness, eyelid changes, and evidence of myositis on muscle biopsy, as well as a coexisting gastric carcinoma.

Gottron papules and a heliotrope rash are pathognomonic of dermatomyositis. Other findings may include periungual telangiectasia;, cuticular overgrowth; nailfold infarcts; poikiloderma, especially over the extensor extremities; a scaly scalp dermatitis; and/or photosensitivity accompanied by proximal muscle weakness. Dermatomyositis is a multisystem disorder and can be associated with several systemic manifestations.

In a review of 42 retrospective case series on inflammatory myopathies, 24% of patients with DM had an associated malignancy. The linkage of HLADqA1∗0301 with anti-p155/140 antibodies in white patients with myositis suggests a possible genetic basis.

Although dermatomyositis may occur before, after, or concurrent with the diagnosis of cancer, the risk of malignancy is greatest within the first 3 years of diagnosis of DM. The most common malignancies are ovarian, lung, gastrointestinal tract, and breast in Western countries; nasopharyngeal carcinoma is commonly associated in certain Asian and African countries. Other reported malignancies include angiotropic lymphoma, urachal carcinoma, and prostate cancer.

Because the risk of an underlying malignancy is significant in patients with DM, an extensive evaluation for malignancy is advisable. The patient’s individual risk factors and the most commonly associated malignancies should guide this evaluation. Factors that predict malignancy include cutaneous necrosis, more severe muscle disease refractory to steroid therapy, and the absence of overlap connective tissue disease features. Anti-p155/140 antibodies have a predictive value for malignancy in adult patients.

Andras and colleagues reported remission of the myositis in 16 of 22 patients after treatment of the underlying malignancy. In addition to treatment of the primary tumor, systemic immunosuppressive agents may improve the associated myopathy; sun protection, topical steroids, and immunosuppressives may benefit the cutaneous manifestations.

Paraneoplastic Pemphigus

Classically, pemphigus refers to mucocutaneous diseases that are characterized by intraepithelial blisters, caused by a loss of normal cell-cell adhesion secondary to autoantibodies against cell-surface proteins. The concept of paraneoplastic pemphigus (PNP) was solidified in the early 1990s when it was observed that an underlying neoplasm was always associated with a certain set of clinically atypical pemphigus patients. In two-thirds of patients, the disease presents before the neoplasm is recognized. The mean age of onset is 59 years and there is no gender predominance.

Clinically, PNP is characterized by severe and intractable stomatitis, along with polymorphic cutaneous eruptions ranging from lichen planus–like or erythema multiforme–like lesions, to the more well-recognized bullae of classic pemphigus. Compared with pemphigus vulgaris, PNP is more likely to involve acral skin. In adults, the most commonly associated malignancies are non-Hodgkin lymphoma and chronic lymphocytic leukemia, and, to a lesser extent, Castleman disease, thymomas, sarcomas, and Waldenstrom macroglobulinemia. In children and adolescents, the associated underlying neoplasm is predominantly Castleman disease.

Immunoglobulin G (IgG) autoantibodies against multiple epithelial proteins critical to cell-cell adhesion (including desmosomes and hemidesmosomes) develop in patients with PNP. These autoantibodies include desmoplakins I and II, bullous pemphigoid antigen 1, envoplakin, periplakin, plectin, and desmoglein 1 and 3. Serum autoantibodies against the plakin proteins are the most diagnostic markers.

Prognosis is poor, and the disease is highly resistant to many immunosuppressive therapies. First-line treatment remains oral corticosteroids, and combination therapy with cyclophosphamide, high-dose intravenous immunoglobulin (IVIG) and/or rituximab is often required. However, even if resolution of the mucocutaneous features of PNP is achieved with successful treatment of the underlying malignancy and immunosuppressive therapy, some patients may develop, and ultimately succumb to, progressive constrictive bronchiolitis obliterans, the cause of which is unclear.

Sweet’s Syndrome

Sweet’s syndrome is the prototype of the neutrophilic dermatoses, and is characterized by the constellation of pyrexia, neutrophilia, tender erythematous cutaneous lesions, and prompt response to corticosteroids. The disease was first described in association with aerodigestive tract infections, and currently is best classified under 3 clinical settings : classic or idiopathic (most frequently associated with streptococcus and yersinia infections, inflammatory bowel disease, or pregnancy), malignancy associated (most commonly acute myelogenous leukemia), and drug induced (most clearly associated with granulocyte-colony stimulating factor and all-transretinoic acid).

Although idiopathic Sweet’s affects predominantly young women, malignancy-associated Sweet’s affects middle-aged men and women equally, and accounts for about 20% to 30% of cases. Besides acute myelogenous leukemia, Sweet’s has been reported with lymphomas, chronic leukemias, myelomas, myelodysplastic syndromes, and a variety of solid tumors (eg, breast and colon). In 60% of cases, the onset of Sweet’s syndrome either precedes or coincides with the discovery of a neoplasm.

Patients typically present with tender, pseudovesicular, or crusted erythematous plaques on the head, neck, and upper extremities, which tend to resolve without scarring (see Fig. 1 C). A nonspecific flulike illness often precedes skin lesions and fever typically develops. The plaques occasionally exhibit true vesicles, bullae, or pustules. In the setting of malignancy, more widespread involvement may be seen. Atypical presentations, such as vesiculobullous lesions and oral pustular lesions that may progress to ulceration, may occur in hematologic disorders such as myelodysplastic syndromes and myelogenous leukemia. Pathergy, the onset of lesions at sites of trauma (eg, needle sticks), is common. Extracutaneous involvement may occur, including involvement of the eyes, lungs, bones, heart, muscle, and central nervous system. Constitutionally, patients may appear very ill, and complain of arthralgias, malaise, headache, and myalgias. Although a peripheral neutrophilia is characteristic, its absence does not exclude the diagnosis, because patients with neutropenia associated with their leukemia or its treatment may develop Sweet’s.

The treatment of choice is systemic corticosteroids. Potassium iodide and colchicine are alternative first-line therapies. Second-line agents include indomethacin, clofazimine, cyclosporine, and dapsone. Recurrence is common, especially in malignancy-associated Sweet’s, and may herald relapse of the underlying cancer.

Necrobiotic Xanthogranuloma

Necrobiotic xanthogranuloma (NXG) is a slowly progressive multiorgan, histiocytic dermatosis associated with paraproteinemia. Clinically, patients present with multiple indurated yellow or violaceous papules and plaques that often involve the periorbital skin. Central atrophy, telangiectasias, ulceration, and scarring may be seen. Lesions may also develop elsewhere on the face, as well as the trunk and proximal extremities (see Fig. 1 D), and may form within scars. Extracutaneous involvement most commonly involves the eye (in up to 81% of patients) ; findings include orbital masses, ectropion, keratitis, and proptosis. Postmortem examination has shown internal organ involvement in NXG, including endocardial lesions. The mean age of onset is 60 years without any gender predilection. Only 75 cases have been reported to date.

A paraproteinemia can be detected in 80% of cases, with IgG-κ monoclonal gammopathy predominating (65%). NXG may be associated with multiple myeloma, plasma cell dyscrasias, and, less frequently, lymphoproliferative disorders and solid tumor malignancies. Roughly one-quarter of patients with associated paraproteinemias go on to develop multiple myeloma.

Treatments with reported benefit in NXG include low-dose chlorambucil, melphalan, cyclophosphamide, radiation, and plasmapheresis. Excision carries a high local recurrence rate (42%) and should be avoided. NXG is typically chronic and progressive. Overall survival is good, but prognosis depends on the degree of extracutaneous involvement and the presence and severity of associated malignancies.

Multicentric Reticulohistiocytosis

The term multicentric reticulohistiocytosis (MRH) was first used by Goltz and Laymon in 1954 to describe cases of non–Langerhan cell reticulohistiocytosis with both cutaneous and systemic manifestations. Characteristic skin lesions and a destructive polyarthritis define this condition. Clinically, firm, skin-colored to red-brown papules and nodules develop over acral surfaces (eg, hands, ears), the head, and skin overlying joints. Alignment of small papules periungually can be seen, referred to as the coral bead sign. A symmetric, erosive arthritis of multiple joints develops and may progress to arthritis mutilans. The joints of the fingers, hands, wrists, and knees are preferentially involved. MRH most commonly affects white women in the fourth decade.

Between 15% and 30% of cases are associated with an underlying malignancy, typically solid tumors of the lung, breast, stomach, or cervix, warranting a malignancy work-up in all patients. However, the course of the skin disease does not parallel the course of the underlying neoplasm and thus some have negated the categorization of this disease as paraneoplastic. The mononuclear cells of this disease exhibit properties of osteoclasts such as the tissue lytic markers of tartrate-resistant acid phosphatase and cathepsin K, and RANKL (receptor activator of nuclear factor κ-B ligand). It has been postulated that histiocytes in MRH may differentiate into osteoclastlike multinucleated giant cells in the skin.

Traditionally, methotrexate, either as sole therapy or in combination with other immunosuppressants, has been the mainstay of treatment. Recently, increased levels of tumor necrosis factor (TNF)α and interleukin (IL)-1β within the synovial fluid of patients with MRH have been shown and a few cases of successful treatment with TNFα antagonists have been reported. Case reports and clinical evidence is starting to accumulate on the use of bisphosphonates in this disease, which may act directly on the mononuclear cells leading to inhibition of RANKL, and therefore inhibiting differentiation of histiocytes into osteoclastlike cells. Although the disease usually spontaneously remits, the destructive cutaneous and articular lesions may lead to significant disfigurement.

Scleromyxedema

Scleromyxedema, or generalized lichen myxedematosus, is one of the mucinous deposition disorders. Diagnosis of scleromyxedema should fulfill the following criteria: (1) generalized papular and sclerodermoid eruption; (2) skin biopsy showing mucin deposition, fibroblast proliferation, and fibrosis; (3) monoclonal gammopathy (IgG-λ paraproteinemia); and (4) the absence of thyroid disease.

Clinically, numerous waxy, firm, tiny papules develop symmetrically and affected areas of skin become sclerotic. The head and neck, hands, upper trunk, and extremities are typically involved. Longitudinal furrows of the glabella and thickened skin with central depressions over the proximal interphalangeal joints (doughnut sign) are characteristic features. Systemic manifestations in scleromyxedema are prevalent, and can resemble those of scleroderma or other rheumatologic diseases. With disease progression, gradual restriction of movement may occur. In contrast with scleroderma, the skin is moveable over the subcutis, and periungual telangiectasias are absent.

Paraproteinemia, most commonly monoclonal IgG-λ, is present in approximately 80% of patients. It does not represent a primary plasma cell dyscrasia, and less than 10% of patients progress to multiple myeloma. There are rare case reports of association with myopathy, including dermatomyositis, and myopathy with hyperthyroidism.

Numerous treatment modalities have been reported in the literature, but often with inconsistent results, frequent relapses, and potentially serious side effects including intralesional corticosteroids, melphalan, phototherapy, systemic retinoids, plasmapheresis, and autologous hematopoietic stem cell transplantation. Improvement with IVIG or thalidomide has also been reported. Overall, scleromyxedema tends to follow a chronic and progressive course and patients may ultimately succumb from systemic complications.

Pancreatic Panniculitis

Pancreatic panniculitis is an uncommon condition affecting 2% to 3% of patients with pancreatic disorders. Clinically, it presents with ill-defined, tender, erythematous to red-brown subcutaneous nodules that may spontaneously ulcerate and drain an oily brown viscous substance. The lesions are typically found on the distal lower extremities; however, in pancreatic panniculitis associated with pancreatic carcinoma, they may be found in other areas of the body as well. Pancreatic panniculitis associated with pancreatic tumor, eosinophilia, and polyarthritis is known as the Schmid triad and is associated with a poor prognosis.

Although pancreatic panniculitis is most commonly associated with acute and chronic pancreatitis of various causes, there are numerous reports of this condition developing in association with pancreatic neoplasia. Associated neoplasms include acinar carcinoma, neuroendocrine carcinoma, and acinar cell cystadenocarcinoma. Although comprising less than 2% of all pancreatic neoplasms, acinar cell carcinoma is associated with pancreatic panniculitis in 10% of cases, making it the most commonly associated neoplasm. Pancreatic panniculitis has also been reported in a case of pancreatic metastasis from gastric carcinoma. The onset of pancreatic panniculitis relative to the diagnosis of the underlying neoplasm is variable; however, it has been reported to predate discovery of the pancreatic neoplasm by up to several months. Pancreatic panniculitis may suggest a more aggressive course of the underlying neoplasm.

The mainstay of treatment of pancreatic panniculitis is removal of the underlying neoplasm, which has been reported in some cases to completely resolve the panniculitis. Octreotide, a somatostatin analogue, has been reported to prevent spread of panniculitis in patients who are not candidates for tumor resection.

Neutrophilic Panniculitis in Myeloproliferative Disorders

In 1982, Leibowitz and colleagues described a 34-year-old woman with a variant of Sweet’s syndrome extending into the subcutaneous fat who was found to have a dyserythropoiesis on bone marrow biopsy. This case was the first description of neutrophilic panniculitis associated with an underlying malignancy. Since then, there have been sporadic case reports of neutrophilic panniculitis associated with several malignancies, most commonly myeloproliferative disorders. Clinically, the lesions are tender, erythematous plaques or nodules that favor the limbs. Characteristically, patients are systemically ill, often with fever, pain, and arthralgia. The incidence of panniculitis in patients with myeloproliferative disorder is unknown; however, it is rare. One study of 2357 patients with multiple myeloma, in which an associated neutrophilic panniculitis was reported, revealed only 1 patient with a skin biopsy revealing panniculitis.

Myeloproliferative disorders associated with neutrophilic panniculitis include myelodysplastic syndrome, acute myeloid leukemia, multiple myeloma, and dyserythropoesis. More recently, there have been case reports of neutrophilic panniculitis associated with metastasis from prostate cancer and breast cancer. Panniculitis has been reported as the presenting sign of hematological malignancy. It has also developed on initiation of certain medications in the setting of hematologic malignancy, specifically all-transretinoic acid in a patient with acute promyelocytic leukemia, imatinib, and subsequently dasatinib, in a single patient with chronic myelogenous leukemia.

The existence of neutrophilic lobular panniculitis as a distinct histopathologic entity has been challenged and may be a presentation of subcutaneous Sweet’s syndrome. High-dose corticosteroids have resulted in rapid clinical improvement of the panniculitis; other antineutrophilic agents such as dapsone and colchicine have also been tried with success.

Palmar Fasciitis and Polyarthritis

Palmar fasciitis and polyarthritis syndrome (PFPAS) was first recognized as a distinct entity by Medsger and colleagues in 1982, when they presented a case series of 6 patients with painful hand contractures and polyarthritis who were found to have ovarian carcinomas. Since then, more than 40 cases of this syndrome have been published in the literature. In most cases, the hands develop diffuse painful swelling and stiffness with subsequent nodular thickening of the palmar fascia. Skin surface changes may include erythema at the periphery of the palms or indurated, reticular erythema over the central palm. Synovitis and polyarthritis favor the small joints of the hand; joint involvement at other locations, such as the shoulders, elbows, wrists, knees, ankles, and feet, has been reported but symptoms are typically less severe. Severity of symptoms can range from mild to completely disabling.

The most common neoplasm associated with PFPAS is ovarian carcinoma; however, many associated malignancies have been reported, including pancreas, lung, colon, prostate, breast, hepatocellular, renal pelvis, uterine cervix, gastric, gastroesophageal, Hodgkin disease, multiple myeloma, and chronic myelogenous leukemia. Several benign conditions have also been associated and, in some cases, no underlying cause has been found. Typically PFPAS develops before diagnosis of the underlying malignancy with reported onset as early as 23 months before diagnosis. In addition, PFPAS has occurred on treatment of gastroesophageal cancer with a matrix metalloproteinase inhibitor.

Radiographs of the affected joints are typically unremarkable except for variable periarticular demineralization and soft tissue swelling. Symptoms of polyarthritis and pain have been reported to improve with treatment of the underlying malignancy, but palmar fibrosis and resulting contractures tend to be persistent. Systemic glucocorticoids have been of modest benefit for symptom relief in several cases but are usually ineffective.

Eosinophilic Fasciitis and Fasciitis-Panniculitis Syndrome

In 1975, Shulman reported a syndrome involving fibrotic thickening of the subcutaneous fat and fascia with variable infiltration of eosinophils and/or peripheral eosinophilia, which was subsequently termed eosinophilic fasciitis. In 1992, Naschitz and colleagues described a series of patients with similar clinical and histologic features to eosinophilic fasciitis; however, they noted that peripheral and tissue eosinophilia were inconsistent findings. They coined the term fasciitis-panniculitis syndrome (FPS), which included eosinophilic fasciitis in addition to other entities involving subcutaneous-fascial fibrosis such as lipodermatosclerosis, chronic graft-versus-host disease, postirradiation injury, and others. Clinically, eosinophilic fasciitis and FPS are characterized by 1 or more areas of sleevelike and/or plaquelike swelling or induration of the skin. The lower extremity is most commonly affected; however, neck, forearm, wrist, and generalized involvement have been reported. Eosinophilic fasciitis is known to display a progression from edema of the affected extremities, then to hyperpigmented peau d’orange skin, then to woody induration with skin tightness. Extracutaneous manifestations occur in 5% to 15% of patients and may include arthritis, hepatitis, pericarditis, colitis, pleuritis, pulmonary fibrosis, esophageal disturbances, thyroid disease, Sjögren syndrome, and Raynaud phenomenon.

The true incidence of malignancy-associated eosinophilic fasciitis and FPS is unknown, although Naschitz and colleagues reported 3 patients in an 8-year period at an institution serving more than 150,000 patients in Israel. Only a small percentage of eosinophilic fasciitis and FPS is associated with malignancy: 4 patients in a series of 52 and 3 patients in a series of 19, respectively. Hematologic malignancies are most commonly associated with eosinophilic fasciitis and FPS, but solid organ tumors have also been reported. Specifically, malignancies associated with eosinophilic fasciitis include myeloproliferative disorder, myelomonocytic leukemia, chronic lymphocytic leukemia, porphyria cutanea tarda, Hodgkin disease, immunoblastic lymphoma, T-cell lymphoma, breast carcinoma, and colorectal carcinoma. Associations with FPS include myelomonocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, Hodgkin disease, T-cell lymphoma, breast carcinoma, prostate carcinoma, gastric adenocarcinoma, and pancreatic carcinoma. The onset of FPS typically precedes the onset of hematological malignancy from months to 3.5 years; however, timing of onset of associated solid organ malignancies was more variable.

Although idiopathic eosinophilic fasciitis and FPS are usually corticosteroid responsive, paraneoplastic eosinophilic fasciitis and FPS are not consistently improved with steroids. Eosinophilic fasciitis and FPS may remit after successful treatment of the neoplasm.